CN100439320C

CN100439320C - Intermediates for preparation of arthropodicidal oxadiazines

Info

Publication number: CN100439320C
Application number: CNB031579167A
Authority: CN
Inventors: G·D·安尼斯; S·F·麦坎; R·沙皮罗
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 1994-04-20
Filing date: 1995-04-17
Publication date: 2008-12-03
Anticipated expiration: 2015-04-17
Also published as: AU687547B2; WO1995029171A1; MX209131B; CN1142922C; CN1059901C; DE69534440D1; ES2171537T3; PT756594E; PL316849A1; US5869657A; DE69535654T2; IL155210A; CA2582172C; IL113412A0; CA2188400A1; IL113412A; JP4263200B2; EP1357107A1; AU2243295A; AU5216898A

Abstract

The invention discloses intermediates for preparing oxadiazile, comprising compounds of formula II, IX and X, wherein each group is defined in the description.

Description

Intermediates for the preparation of * diazines

The present application is a divisional application of an invention patent application (divisional application) with application number 00103632.7 entitled "intermediate for producing oxadiazine and process for producing the same", filed on 23/2/2000.

This application is a divisional application of the invention patent application PCT/US95/04321 entitled "preparation of arthropodicidal oxadiazines", filed on 17.4.1995, originally filed on 18.10.1996, and filed in China under the application number 95192654.3.

The present invention relates to the preparation of arthropodicidal (artropodicidal) oxadiazines and intermediates thereof.

Arthropodicidal oxadiazines are disclosed in WO9211249 and WO 9319045. However, the preparation of these compounds must be improved to be suitable for economical commercial production. Thus, the present invention provides a convenient route to the preferred arthropodicidal oxadiazines.

The present invention relates to a process for the preparation of a compound of formula I, which is racemic or enantiomerically enriched at the chiral centre:

wherein R is¹Is F, Cl, or C₁-C₃Fluoroalkoxy, and R²Is C₁-C₃An alkyl group, the method comprising: (a) will renOptionally enantiomerically enriched compounds of formula II:

with a compound of formula III in the presence of an acid catalyst:

H₂N-NHR³

III

to produce a compound of formula IV:

wherein R is³Is a protecting group such as CO₂CH₂(C₆H₅) Etc.;

(b) reacting a compound of formula IV with a bis (C)₁-C₃Alkoxy) methane in the presence of a Lewis acid to form a compound of formula V

(c) Hydrogenating the compound of formula V to produce a compound of formula VI

And

(d) reacting a compound of formula VI with a compound of formula VII:

to produce a compound of formula I having virtually the same absolute configuration as the compound of formula II.

The invention also relates to a process for the preparation of a compound of formula I enantiomerically enriched at the chiral centre, which process comprises steps a-d, wherein the compound of formula II in step a is enantiomerically enriched with the same configuration as the desired compound of formula I.

The invention also relates to a process for the preparation of a compound of formula I enantiomerically enriched at the chiral centre, which process comprises steps a-d and further comprises

(i) Reacting para-substituted phenyl acetyl halide with ethylene in the presence of Lewis acid to generate the compound shown in the formula VIII

(ii) Reacting VIII with a peroxyacid to produce a compound of formula IX

(iii) Mixing IX with C₁-C₃Alcohol in the presence of an acid catalyst to form a compound of formula X

(iv) Reacting X with a base to produce a compound of formula XI

And

(v) reacting XI with hydrogen peroxide in the presence of a chiral base to generate enantiomerically enriched II;

wherein

Reacting the enantiomerically enriched II from step v in step a, wherein R¹And R²As previously defined.

The invention also relates to each of the process steps a, b, c and d and to a multi-step process a, b; a, b, c; b, c; b, c, d; and c, d.

The invention also relates to a single process step v for the preparation of the enantiomer of formula II from the compound of formula XI; preparing a compound of a formula II by a five-step i-v method; four step i-iv process for preparing compounds of formula XI from para-substituted phenylacetic acid halides; preparing a compound of formula IX in a two-step i-ii process; a single process step ii to prepare a compound of formula IX; and, a two step ii-iii process for preparing a compound of formula X.

The invention also relates to the (+) enantiomer of a compound of formula II:

wherein

R¹Selected from the groups F, Cl and C₁-C₃Fluoroalkoxy, and R²Is C₁-C₃Alkyl, the compound being virtually pure (+) enantiomer.

The invention also relates to racemic and enantiomerically enriched compounds of formulae IV, V and VI;

wherein

R¹Is F, Cl, or C₁-C₃Fluoroalkoxy, and R²Is C₁-C₃Alkyl, and R³Is CO₂CH₂(C₆H₅)。

The invention also relates to compounds of formula VII.

The invention also relates to compounds of formulae XI and X

Wherein

R¹Selected from the groups F, Cl and C₁-C₃Fluoroalkoxy, and R²Is C₁-C₃An alkyl group.

In the above definitions, the term "halide" refers to fluorine, chlorine, bromine or iodide. The term "C₁-C₃Alkyl "denotes straight-chain or branched alkyl having 1, 2 or 3 carbon atoms and denotes methyl, ethyl, n-propyl or isopropyl. The term "C₁-C₃Alkoxy "refers to methoxy, ethoxy, n-propoxy or isopropoxy. The term "C₁-C₃Fluoroalkoxy "refers to methoxy, ethoxy, n-propoxy or isopropoxy partially or fully substituted with fluorine atoms, including, for example, CF₃O and CF₃CH₂And O. The term "C₁-C₃The alcohol "refers to methyl, ethyl, n-propyl or isopropyl alcohol.

Preferred compounds of the formulae IV, V and VI are those in which R²Is methyl and R¹Is chlorine, CF₃O or CF₃CH₂A compound of O. Most preferredThe compound is

Benzyl [ 5-chloro-2, 3-dihydro-2-hydroxy-2- (methoxycarbonyl) -1H-inden-1-ylidene ] hydrazinecarboxylate (accession IVa);

2- (benzyl) -7-chloroindeno [1, 2-e ] [1, 3, 4] diazine-2, 4a (3H, 5H) -dicarboxylic acid 4 a-methyl ester (registered Va); and

7-chloro-2, 5-dihydroindeno [1, 2-e ] [1, 3, 4] diazine-4 a (3H) -Carboxylic acid methyl ester (registered VIa).

Preferred compounds of the formulae II, IX and X are those in which R²Is methyl and R¹Is chlorine, bromine, CF₃O or CF₃CH₂A compound of O. The most preferred compounds are

(+) -5-chloro-1, 3-dihydro-2-hydroxy-1-oxo-2H-indene-2-carboxylic acid methyl ester (registered as (+) IIa);

2-carboxy-5-chlorophenylpropionic acid (accession IXa); and

methyl 5-chloro-2- (methoxycarbonyl) phenylpropionate (accession Xa).

Detailed description of the invention

One aspect of the present invention relates to a process for the preparation of a compound of formula I, comprising four steps a-d, generally as follows:

step a) is carried out by reacting II (prepared, for example, from a substituted 2, 3-dihydro-1-indanone, such as 5-chloro-1- (2, 3-indanone), as described in detail in WO 9211249) with about one molar equivalent of formula III in the presence of an acid catalyst, such as p-benzenesulfonic acid, sulfuric acid or acetic acid, to form IV, optionally in an inert solvent such as methanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane or the like. Typical reaction conditions include a temperature of about 40 ℃ to 120 ℃, preferably 65 ℃ to 85 ℃, for a time of about 0.5 to 25 hours. Compound IV can be recovered by standard methods such as filtration, optionally after dilution of the reaction mixture with water. Alternatively, IV can be extracted with a solvent and used in the next reaction without isolation.

Step b) by reacting IV with bis (C)₁-C₃Alkoxy) methane such as dimethoxymethane or diethoxymethane in the presence of a lewis acid to form V, optionally in the presence of an inert solvent such as dichloromethane, 1, 2-dichloroethane, chlorobenzene, α, α, α -trifluorotoluene, and the like. Two (C)₁-C₃Alkoxy) methane may be in molar excess. The Lewis acid comprises P₂O₅，BF₃And SO₃Generally 0.9 to 4.0 molar equivalents (relative to V) are required for best results; also included are the triflates of metals (especially scandium, ytterbium, yttrium and zinc), which may be used in about 0.1 to 0.5 molar equivalents relative to V. The most preferred Lewis acid for this step is P₂O₅And SO₃；SO₃Can be in the form of a complex such as DMF & SO₃(DMF is dimethylformamide) form. Typical reaction conditions include a temperature of about 20 ℃ to 150 ℃, preferably 50 ℃ to 60 ℃, a pressure of about 100 ℃ to 700kPa, preferably 100 ℃ to 300kPa, and a time of about 0.5 to 48 hours. When using non-lossy Lewis acids, such as the triflates of rare earth metals, it is preferred to remove by-product C continuously by distillation during the reaction₁-C₃An alcohol. Compound V can be recovered by standard methods such as filtration and used in the next reaction without further purification. On the other hand, when a metal salt of triflic acid is used as the lewis acid, V may be recovered from the organic phase by concentrating the reaction mass, optionally diluting with an inert solvent immiscible with water such as ethyl acetate, washing with water to remove the metal salt of triflic acid, concentrating the organic phase and optionally inducing crystallization of V from the organic phase by addition of a suitable solvent such as aqueous methanol, hexane and the like.

Step C) is carried out by contacting V with hydrogen, either from a hydrogen source or preferably molecular hydrogen itself, over a hydrogenolysis metal catalyst such as palladium, preferably supported on a material such as activated carbon, in an inert solvent such as methyl acetate, ethyl acetate toluene, diethoxymethane or C₁-C₃VI is formed by reaction in the presence of an alcohol. Typical reaction conditions include a temperature of about 0 ℃ to 30 ℃, preferably about 20 ℃ andthe pressure is about 105 kPa to 140kPa, preferably about 35kPa, for about 3 hours. Compound VI can be prepared by standard methods such as filtration and collection of the palladium for subsequent batch recycle, separation of the organic phase and concentration and induction of crystallization of VI by removal of the solvent, optionally by addition of C₁-C₃Alcohol, acetonitrile or aliphatic hydrocarbons such as hexane are recovered. The compound VI is preferably used in the next reaction without isolation from solution in the organic phase.

Step d) forms I by reacting VI with about 1 molar equivalent of VII, optionally in the presence of about 1.0-1.5 molar equivalents (relative to VII) of an acid scavenger such as trialkylamine, pyridine or, preferably, sodium carbonate or sodium bicarbonate in aqueous solution in an inert solvent such as toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, 1, 2-dichloroethane, diethoxymethane, etc. Typical reaction conditions include a temperature of about 0 ℃ to 30 ℃ and a time of about 0.2 to 2 hours. Compound I can be obtained by standard methods such as washing the reaction mixture with aqueous acid and aqueous sodium chloride, concentrating the organic phase and inducing crystallization of I from the organic phase, optionally by addition of C₁-C₃Alcohol, water, alcohol-water mixtures or aliphatic hydrocarbons such as hexane are recovered. Steps c and d can be combined in a single reaction tank by adding VII and optionally an acid scavenger in the hydrogenolysis of V. According to this method, compound VI, once formed, is acylated to give I. Typical solvents for combined steps c and d are methyl acetate, ethyl acetate, toluene, xylene, dichloromethane, 1, 2-dichloroethane and the like. The acid scavenger may be a trialkylamine such as tripropylamine tributylamine, diisopropylethylamine, etc., or a solid inorganic compound such as sodium bicarbonate, calcium oxide, sodium pyrophosphate, trisodium citrate, etc.

The reaction steps a-d are carried out with the configuration of the chiral centre substantially retained. In a preferred embodiment, the compound of formula II used in step a is enantiomerically enriched, thus providing an enantiomerically enriched compound of formula I of the same absolute configuration. Enantiomeric enrichment refers to a batch sample of a compound containing an excess of the (+) or (-) enantiomer and a mixture of enantiomers including up to and including 100% pure enantiomer greater than 1 to 1 (racemic). Thus, for example, an enriched compound having 25% (-) and 75% (+) enantiomers is considered to be a mixture of the 50% racemate and the 50% pure (+) enantiomer, and is referred to as the (+) enantiomer with 50% enantiomeric excess. In a particularly preferred embodiment of the invention, the compound of formula II is enriched with the (+) enantiomer, which results in the compound of formula I being enriched with the (+) enantiomer, which has been found to be the more arthropodicidally active enantiomer. The enrichment of the compound of formula II is preferably at least 10% and more preferably at least 20% of the (+) enantiomer.

The enantiomerically enriched compounds of formula II may be prepared, for example, by physical separation of the enantiomers of a racemic mixture according to standard methods. However, this process is difficult to handle in large quantities and is often wasteful, since the undesired enantiomer must be discarded. In a particularly preferred embodiment of the invention, the enantiomerically enriched compound of formula II is prepared by a five-step enantioselective process comprising i-v. "enantioselectivity" refers to the preferential formation of the desired enantiomer of a chiral product, although such preference need not be exclusive. Steps i-v operate generally as follows.

Step i) VIII is prepared by reacting an appropriately substituted phenylacetic halide, which is commercially available (e.g., from Spectrum chemical Manufacturing Co., Ltd.) or prepared from an acid by known methods and optionally generated in situ, with about 1 to 4 molar equivalents, preferably 2 molar equivalents, of ethylene gas and about 0.9 to 1.5 molar equivalents of a Lewis acid such as aluminum chloride in about 3 to 10 parts by weight of an inert solvent such as dichloromethane, dichloroethane, carbon disulfide, or o-dichlorobenzene. Typical reaction conditions include a temperature in the range of about-20 ℃ to +30 ℃, preferably-5 ℃ to 0 ℃, a pressure in the range of about 60-400kPa and a reaction time of about 0.5-8 hours. The compound VIII can be isolated by standard methods or, when the solvent is appropriate, for example, when the solvent is dichloromethane or dichloroethane, the reaction mixture can be used directly in the next step without isolating VIII. In a preferred embodiment, the reaction mixture of step i is used in step ii without isolation of VIII.

Step ii) IX is formed by reacting VIII with about 2.5 to 3.5 equivalents of a peroxycarboxylic acid, preferably peroxyacetic acid, in an inert solvent such as acetic acid, dichloromethane, o-dichlorobenzene, or 1, 2-dichloroethane. Typical reaction conditions include a temperature range of about 15 ℃ to 55 ℃, preferably 25 ℃ to 45 ℃, and a reaction time of about 5-35 hours. The lower temperature is maintained for safety reasons. Preferably, but not necessarily, the reaction is carried out in 0.5 to 2.5 molar equivalents of a buffering agent such as sodium acetate. The rate of peroxycarboxylic acid addition to the solution of VIII is controlled to avoid accumulation of excess peroxycarboxylic acid. The product can be isolated, for example, by quenching with water, optionally adding a reducing agent such as sulfur dioxide to remove excess oxidizing agent, and filtering. If necessary, the pH can be adjusted to below 3 before the product is filtered.

Step iii) X is formed by standard esterification methods of IX. In a preferred embodiment, IX is reacted with an alcoholic solvent (about 2 to 20 parts by weight) in the presence of about 1 to 20 molar equivalents of the corresponding carbonate derivative of the alcohol as dehydrating agent and about 0.001 to 0.2 molar equivalents of an acid, such as sulfuric acid or p-toluenesulfonic acid catalyst. Wherein typical reaction conditions include a temperature in the range of about 75 ℃ to 105 ℃, a pressure in the range of about 100 kPa to 500kPa and a reaction time in the range of about 10 to 30 hours. Compound X can be isolated by standard methods. On the other hand, the reaction mixture can be used in the next reaction without isolation. Preferably, X is not isolated prior to step iv.

Step iv) forming XI by reacting X with a strong base such as an alkali metal alkoxide or hydride in a suitable solvent such as the corresponding alcohol, benzene, toluene or xylene. Typical reaction conditions include a temperature of about 60 ℃ to 90 ℃, a pressure of about 100 kPa to 500kPa and a reaction time of about 0.5 to 10 hours. The product may be recovered and isolated as an alkali metal salt, for example, by filtration. Alternatively, the product may be first neutralized with an acid such as glacial acetic acid or dilute aqueous mineral acid; and then isolated by, for example, filtration or extraction.

Step v) enantiomerically enriched II is formed by reacting XI with about 0.9 to 1.5 equivalents of a hydroperoxide such as hydrogen peroxide and a monoether of hydrogen peroxide in the presence of about 0.001 to 1.5 equivalents of an optically active amine base and optionally an inert solvent. Preferred monoethers of hydrogen peroxide include t-butyl hydroperoxide, cumene hydroperoxide and combinations thereof. Suitable solvents include aliphatic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene, xylene, ethylbenzene, 1, 3, 5-trimethylbenzene and cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane and o-dichlorobenzene, ketones such as methyl ethyl ketone, methyl isobutyl ketone, and methyl isopropyl ketone, esters such as methyl acetate, ethyl acetate, isopropyl acetate, and ethers such as diethyl ether and tetrahydrofuran. Aromatic hydrocarbon solvents are preferred. Typical reaction conditions include a reaction temperature range of about-5 ℃ to 50 ℃ and a reaction time of about 2 hours to 8 days. The amine base is preferably cinchona alkaloid or a derivative thereof. Preferably, for the production of II enriched with the (+) enantiomer (designated as (+) II), the cinchona alkaloid is cinchonine, quinidine, the corresponding dihydro derivative of cinchonine or quinidine and any combination of the above; wherein the chiral alkaloid has [8- (R), 9- (S) ] configuration. The compound of formula II enriched with the (-) enantiomer is obtained by using a base such as cinchonidine, quinine and its derivatives, which has the [8- (S), 9- (R) ] configuration. The product may be passed through standard procedures including filtration, optionally followed by either dilution with a sufficient amount of aqueous acid to remove the catalyst or with a non-polar solvent such as hexane. Alternatively, the product mixture may be diluted with a polar, water-immiscible solvent such as ethyl acetate, washed with aqueous acid to remove the catalyst, concentrated and crystallized. Optionally, II can be triturated or recrystallized with a suitable solvent, such as isopropyl acetate, to separate the pure enantiomer from the enantiomerically enriched mixture.

In a preferred embodiment, the solvents in step v are those in which the compound of formula XI has substantially greater solubility than the corresponding compound of formula II. With this solvent, II will precipitate and can be recovered by filtration, and the filtrate containing any dissolved II, unreacted XI and catalyst can be conveniently recycled to the next batch. The solvent is also preferably immiscible with water so that the filtrate can be washed with aqueous base and/or water to reduce the amount of acidic impurities and water soluble byproducts before being used in the next batch. Recycling the filtrate minimizes product losses and provides for more efficient catalyst utilization. Aromatic hydrocarbons such as xylene are particularly preferred solvents for this mode, especially for the preparation of compounds such as IIa.

Example 1

Description of steps a-d to form a compound of formula I.

Step a: formation of benzyl [ 5-chloro-2, 3-dihydro-2-hydroxy-2- (methoxycarbonyl) -1H-inden-1-ylidene ] hydrazinecarboxylate (Compound IVa).

To a 1 l three-necked flask equipped with an upper stirrer, thermometer, reflux condenser, and nitrogen inlet were charged 87 g (0.363 mol) of methyl 5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate, 63.5 g (0.380 mol) of benzyl hydrazinecarboxylate (from lancaster Synthesis), 1.8 g (0.01 mol) of p-toluenesulfonic acid monohydrate, and 300 ml of methanol. The slurry was heated to reflux (67 ℃) to give an organic solution from which the product gradually precipitated. After 14-16 hours, the mixture was cooled to 5 ℃ and filtered. The filter cake is washed with 100 ml of cold methanol and dried under vacuum at 60 ℃ for 2 hours under nitrogen flushing to give 135 g (96% based on indene carboxylate) of an IVa white crystalline solid. Analytical samples were prepared by recrystallization from acetonitrile, mp187-188 ℃;

¹H NMR(CDCl₃)δ3.23(d，1H，J＝18Hz)，3.48(d，1H，J＝18Hz)，3.7(s，3H)，4.58(br s，1H)5.19(br AB q，2H)，7.18(d，1H)，7.25(d of d，1H)，7.45(m，5H)，7.75(br d，1H)，9.55(br s，1H).

the product showed almost no Z- (cis-) isomer.

Step b: formation of 2- (benzyl) -7-chloroindeno [1, 2-e ] [1, 3, 4] diazine-2, 4a (3H, 5H) -dicarboxylic acid 4 a-methyl ester (Compound Va).

To a dry 1 l three-neck flask equipped with an upper stirrer, thermometer, reflux condenser, and nitrogen inlet was added 42 g of diatomaceous earth, 500 ml of 1, 2-dichloroethane, and 100 ml of dimethoxymethane. Phosphorus pentoxide (42 g, 0.31 mol) was added under nitrogen and external cooling (20 ℃ bath), and the mixture was stirred at 20 ℃ to 25 ℃ for 15 minutes before 97 g (0.25 mol) of IVa was added in portions. The mixture was heated at 55-60 ℃ for 2 hours and then filtered. The filter cake was washed with two 100 ml portions of 1, 2-dichloroethane and the combined filtrates were reduced in volume to about 150 ml by distillation. The pH was raised to about 1.5 to about 4 by adding about 5 g NaOAc in 300 ml of methanol and the remaining dichloroethane was removed by distillation of about 150 ml of solvent. About 30 ml of water are then added and the mixture is cooled to 5 ℃ and filtered. The filtered product was washed with 100 ml of cold methanol and air-dried on the filter overnight to give 89 g (89% based on IVa) of Va. Analytical samples were prepared by recrystallization from isopropanol, mp122-124 ℃;

¹H NMR(CDCl₃)δ3.16(d，1H，J＝16Hz)，3.42(d，1H，J＝16Hz)；3.64(s，3H)，5.12(d，1H，J＝10Hz)，5.26(AB q，2H，J＝12Hz)，5.53(br，d，1H，J＝10Hz).7.2-7.45(m，7H)，7.65(d，1H，J＝9Hz).

step c: formation of 7-chloro-2, 5-dihydroindeno [1, 2-e ] [1, 3, 4] diazine-4 a (3H) -Carboxylic acid methyl ester (Compound VIa).

A1L three-necked flask equipped with a magnetic stirrer, a thermometer, a pH electrode, and a gas inlet valve with a three-way stopcock was purged with nitrogen and charged with 27.3 g (0.13 mol) of citric acid monohydrate, 100 mL of water, 10.4 g (0.13 mol) of 50% aqueous sodium hydroxide solution, 0.6 g of 5% palladium on carbon, 500 mL of methyl acetate, and 52.0 g (0.13 mol) of Va. The reaction vessel was purged with nitrogen and the mixture was stirred vigorously at 5 ℃ to 10 ℃ for about 3 hours while passing hydrogen under the liquid surface. The reaction was monitored by Va disappearance in HPLC; when the reaction was complete (about 4 hours), the reaction vessel was purged with nitrogen, the palladium on carbon was filtered over a pad of celite and rinsed with 50 ml of methyl acetate and 20 ml of water. The filtrate was separated and the organic phase containing VIa was used directly in the next step. In a separate operation, the process of step c above is repeated and VIa is isolated by removing about 400 ml of solvent by distillation, adding about 100 ml of hexane, filtering and suction-drying the crystalline product, mp124 ℃ -127 ℃;

¹H NMR(CDCl₃)δ3.18(d，1H，J＝17Hz)，3.40(d，1H，J＝17Hz)，3.65(d，3H)，4.43(d，1H，J＝7Hz)，4.79(d，1H，J＝7Hz)，6.10(br s，IH)，7.25(m，2H)，7.54(d，1H，J＝8 Hz).

step d: formation of methyl 7-chloro-2, 5-dihydro-2- [ [ (methoxycarbonyl) [4- (trifluoromethoxy) -phenyl ] amino ] carbonyl ] indeno [1, 2-e ] [1, 3, 4] diazine-4 a (3H) -carboxylate (Compound Ia).

To the VIa-containing organic phase from step c was added saturated aqueous sodium bicarbonate (140 g, about 0.15 mol), followed by 41 g (0.14 mol) (chlorocarbonyl) [4- (trifluoromethoxy) phenyl ] carbamic acid methyl ester (compound VII), and the mixture was stirred at 10 ℃ to 15 ℃ for about 1 hour. The organic phase was separated, dried (magnesium sulfate), concentrated in vacuo to remove about 400 ml of methyl acetate and the residual solvent was exchanged by distillation with 300 ml of methanol until the heating temperature reached 64 ℃. The mixture was cooled to 5 ℃ and the product was filtered, washed with 70 ml of cold methanol, suction-dried to give 58 g of Ia (85% overall yield based on Va from step c), mp139-141 ℃;

¹H NMR(CDCl₃₎δ3.25(d，1H，J＝16Hz)，3.48(d，1H，J＝16Hz)，3.70(s，3H)，3.71(s，3H)，5.20(d，1H，J＝10Hz)，5.69(d，1H，J＝10Hz)，7.2-7.4(m，6H)，7.50(d，1H，J＝8 Hz).

example 2

Description of steps i-v to form a compound of formula II.

Step i: formation of 6-chloro-3, 4-dihydro-2 (1H) -naphthalene (Compound VIIIa).

To the flask were added 34 g (0.20 mol) of 4-chlorophenylacetic acid (PCPA) and 150 ml of 1, 2-dichloroethane. The suspension is stirred, 25 g (0.21 mol) of thionyl chloride are added and the resulting solution is heated at 80 ℃ to 90 ℃ for 2 to 3 hours. A distillation head was fitted and 25 ml of solvent were distilled off to remove residual sulphur dioxide and hydrogen chloride. The light orange acid chloride solution was cooled to-5 ℃, aluminum chloride (30 g, 0.22 mol) was added at-5 ℃ to 0 ℃, and the distillation apparatus was replaced with a bulb. Ethylene gas (12 g, 0.43 mol) was added in portions to the balloon while maintaining the temperature at-5 ℃ to 0 ℃, and the red solution was gradually transferred through a cannula into 200 ml of 5 ℃ quench water at a rate that maintained the quench temperature at 20 ℃ to 30 ℃. After stirring the mixture at 25 ℃ for 1 hour, the lower organic layer containing VIIIa was separated and washed with 100 ml of 5% aqueous HCl.

Step ii: formation of 2-carboxy-5-chlorophenylpropionic acid (compound IXa).

The solution of VIIIa from the previous step is added to a flask equipped with an upper stirrer. Sodium acetate (16 g, 0.20 mol) was added to the kettle and the mixture was stirred while cooling at 25-30 ℃ 114 g (0.60 mol) of 32% peracetic acid was added continuously from a constant speed dropping funnel over 3-4 hours. The mixture was stirred at 25 ℃ for another 20 hours and then 300 ml of 0.8n hcl was added and the resulting slurry was cooled to 5 ℃. The mixture was filtered, washed with cold 5% aqueous sodium bisulfite and water, blotted dry and dried overnight in a vacuum oven at 50 ℃ under reduced pressure to give 35-36 g (76-78% yield based on PCPA) of a 99% pure IXa white crystalline solid, m.p.156-158 ℃.

Step iii: formation of methyl 5-chloro-2- (methoxycarbonyl) phenylpropionate (Compound Xa).

To a flask equipped with a thermometer and an upper stirrer were added 45.7 g (0.200 mol) of IXa, 5 ml of methanol, and 100 ml of dimethyl carbonate. Sulfuric acid (1 g) was added and the mixture was stirred under nitrogen at 85 ℃ for 20 hours. The acid was neutralized with 3 grams of 25% sodium methoxide solution and a large amount of dimethyl carbonate (DMC) was distilled from the reaction flask. Methanol (100-. The product of this step was carried directly to the next step without isolation.

Step iv: formation of 5-chloro-1-oxo-2, 3-indan-2-carboxylic acid methyl ester (Compound XIa).

In the last step, after removal of most of the DMC, a further 150 ml of methanol are added to the methanol solution of Xa, followed by 47.5 g (0.22 mol) of 25% sodium methoxide in methanol. The solution was maintained at 70 ℃ and methanol was distilled off to the minimum content level required for effective stirring. When the reaction was complete, the mixture was cooled to room temperature. Acetic acid (3 g, 0.05 mol) was added followed by sufficient 1n hcl to bring the pH to 5-6. The mixture was cooled to 5 ℃ and filtered, and the crude solid was washed with water and then cold hexane to give 40-42 g (89-93% yield) of XIa as an off-white solid m.p.80-82 ℃.

Step v: formation of (+) methyl 5-chloro-1, 3-dihydro-2-hydroxy-1-oxo-2H-indene-2-carboxylate (compound (+) IIa).

10.0 g XIa, 17 ml (51 mmol) of a 3.0M solution of tert-butyl hydroperoxide in isooctane, 70 ml of isopropyl acetate and 0.2g of cinchonine (R) ((R))

Chemical Co.) was stirred at room temperature for 6 days. To the mixture was added about 100 ml of ethyl acetate, 30 ml of dilute aqueous sodium bisulfite and 20 ml of 2n hcl. The mixture was shaken and separated and the organic extract was washed successively with water and brine. The solvent was removed in vacuo and the crude solid product was washed with hexane to give 7.31 g IIa (68% yield) with an enantiomeric ratio of 72% (+) to 28% (-), as determined by HPLC using a chiral column. Recrystallizing (+) enriched IIa from isopropyl acetate to obtain 4-5 g of pure (+) IIa, m.p.163-165 ℃;

[α]_D ²⁵+115.1°(CHCl₃，c＝1.0)；¹H NMR(CDCl₃)δ3.21(d，1H，J＝18Hz)，3.67(d，1H，J＝18Hz)，3.72(s，3H)，4.07(s，1H)，7.38(d of d，1H，J＝8 and 1 Hz)，7.47(d，1H，J＝1Hz)，and 7.70(d，1H，J＝8Hz).

example 3

Description of a further operation of steps a-d starting from enantiomerically enriched IIa and forming enantiomerically enriched Ia.

Step a: formation of (+) IVa

To a 1 liter single neck flask equipped with a dean-Stark apparatus and nitrogen inlet was charged 75 g (0.312 mole) of (+) IIa (50% d enantiomeric excess), 54.6 g (0.358 mole) of benzyl hydrazinecarboxylate, 1.78 g (0.0094 mole) of p-toluenesulfonic acid monohydrate (b: (b))Chemical company), and 275 ml of 1, 2-dichloroethane. The slurry was heated to reflux to give an organic solution from which the product gradually precipitated. The aqueous phase collected in the dean-Stark trap was removed. After 2 hours, the mixture was cooled to room temperature. The reaction mixture was used directly in step b.

Step b: formation of (+) Va

To a 2 liter three neck flask equipped with an upper stirrer, thermometer, reflux condenser, and nitrogen inlet was added 88.5 grams of diatomaceous earth () And 300 ml of 1, 2-dichloroethane. Phosphorus pentoxide (88.5 g, 0.623 mol) was added followed by 120 ml of dimethoxymethane. A slurry of (+) IVa in 1, 2-dichloroethane from step a is then added. The mixture was heated at 35-40 ℃ for 5 hours, then cooled to 30 ℃ and filtered. The filter cake was washed with 135 ml of 1, 2-dichloroethane and the combined filtrates were evaporated to a minimum volume. Methanol was added to continue the distillation. When all of the 1, 2-dichloroethane was removed and about 500 ml of methanol remained in the kettle, the distillation was stopped and the kettle was cooled to 45 ℃. The product began to precipitate and 120 ml of water were added. Cooling to 20 ℃ is continued. The mixture was filtered and the filter cake was washed with 370 ml of 3: 1 methanol/water. Mixing the solid inVacuum drying at 80 ℃ overnight gave 100.5 g (80.5% yield over two steps) of (+) Va. It is composed of¹The HNMR spectrum is consistent with that of Va obtained in example 1. The purity thereof by HPLC measurement was 99.3%. Chiral HPLC analysis indicated an enantiomeric excess of the (+) enantiomer of 43%.

Step c: formation of compound (+) VIa.

A500 ml three-necked flask equipped with a magnetic stirrer, thermometer, and stopcock gas inlet valve was purged with nitrogen and charged with 50 ml of methyl acetate, 50 ml of 0.5M sodium dihydrogen phosphate buffer solution (pH3.5), and 0.2g of 50% water-wet 5% palladium on carbon. The biphasic suspension was stirred at room temperature for 0.5 h. In a separate flask, 10 g (0.025 mol) (+) Va was added to 50 ml of methyl acetate under nitrogen, heated at 35 ℃ and stirred until dissolved. A solution of (+) Va was added to the suspension of Pd catalyst and the mixture was cooled to 10 ℃. The reaction vessel was evacuated and the mixture was stirred vigorously at 10 ℃ while passing hydrogen under the liquid surface. The reaction was monitored by TLC and by the disappearance of (+) Va on GC. When the reaction was complete (about 1.5 hours), the reaction vessel was evacuated and purged with nitrogen, the reaction mixture was filtered through a pad of celite, and the filter cake was washed with 20 ml of methyl acetate. The liquid phase is separated and the methyl acetate phase containing (+) VIa is carried directly to step d.

Step d: formation of (+) Ia

The methyl acetate solution from step c containing (+) VIa was added to a solution of 3 grams of sodium bicarbonate in 38 ml of water. The mixture was cooled to 10 ℃ under nitrogen and 7.43 g (0.025 mol) of VII was added in one portion. The reaction mixture was stirred at 10 ℃ for 1 hour. The methyl acetate phase was separated and concentrated under vacuum to remove about 100 ml of solvent. 50 ml of methanol was added and the slurry was evaporated to remove residual methanol and the methyl acetate/methanol azeotrope. Finally 50 ml of methanol are added and the suspension is heated to reflux. Celite (0.4 g) was added while heating was continued, then 17 ml of water was added dropwise. The resulting slurry was cooled, filtered, washed with 33 mL of 2: 1 methanol/water, and dried under vacuum to give 11.16 g enriched (+) Ia (78%, based on total yield of step c and step d at Va). Analysis by chiral HPLC showed an excess of 42% for the (+) enantiomer.

Example 4

Step c and step d.

Step c: formation of VIa

A1L three-necked flask equipped with a magnetic stirrer, a thermometer, and a gas inlet valve with a three-way stopcock was purged with nitrogen and charged with 580 mL of methyl acetate, 0.164 g of sodium acetate (2 mol%), and 0.8 g of 5% palladium on carbon catalyst. Approximately 200 ml of solvent were removed by distillation and the resulting dried solvent/catalyst suspension was cooled to 50 ℃ and 40.0 g (0.1 mol) of Va was added in one portion. The mixture was stirred to dissolve Va, then cooled to room temperature. The reaction vessel was flushed with nitrogen and the mixture was then stirred vigorously at room temperature while passing hydrogen under the liquid surface. The reaction was monitored as Va disappearance. When the reaction was complete (about 3.0 hours), the reaction vessel was evacuated and purged with nitrogen, the palladium on carbon was filtered over a pad of celite and rinsed with 50 ml of dry methyl acetate. The filtrate was used directly in step d.

Step d: formation of Ia

The methyl acetate solution containing VIa from step c was combined with a solution of 12 g sodium bicarbonate in 150 ml water. The mixture is cooled to 10 ℃ under nitrogen and 29.7 g (0.1 mol) of compound VII are added portionwise over 0.5 h; the reaction mixture was stirred at 10 ℃ to 15 ℃ for about 1 hour more. The methyl acetate phase was then separated and concentrated under vacuum to remove about 400 ml of solvent. Methanol (50 ml) was added and the solvent was removed under vacuum. 70% aqueous methanol (100 g) was then added and the mixture was stirred for 45 minutes while cooling in an ice bath. The product was filtered, washed with 25 ml of cold 70% aqueous methanol and dried in vacuo to give 51 g (86%, total yield of Va based on 88.9% purity by HPLC), mp135-138 ℃.

Example 5

Another operational description of step v.

Step v: formation of compound (+) IIa.

11.25 g (50 mmol) of Va, 70 ml of mixed xylene, and 1.4 g (4.8 mmol) of cinchonine (C)Chemical Co.) was stirred under nitrogen and 7.0 g (70 mmol) of 90% aqueous tert-butyl hydroperoxide(s) was addedChemical Co.). The resulting solution was stirred at room temperature for 24 hours, during which time the product began to crystallize. The reaction mixture is then diluted with 100 ml of ethyl acetate and washed successively with two 50 ml portions of saturated aqueous sodium bicarbonate solution, 50 ml of 1N aqueous hydrochloric acid solution, and 50 ml of saturated aqueous sodium bisulfite solution. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 10.6 g of enriched (+) IIa (86% purity, 76% yield based on Va). Chiral HPLC analysis showed the enantiomeric excess of the (+) enantiomer to be 45%.

Example 6

Another operational description of step b.

Step b: formation of compound Va.

To a dry 500 ml four-necked flask equipped with an upper stirrer, thermometer, and two gas inlets was added 49.9 g (0.128 mol) of IVa and 250 ml of diethoxymethane. The mixture was cooled to-10 ℃ and the reaction vessel was evacuated (-24 cmHg pressure). Sulfur trioxide gas is introduced into the cooled reaction vessel at a rate such that the temperature of the reaction mixture is maintained between-10 ℃ and 0 ℃. When the dropping was complete, nitrogen was introduced to release the vacuum. The mixture was warmed to room temperature, stirred for 4.75 hours, 50 ml of water was added at room temperature with good stirring and stirred for a further 2 hours. The mixture is filtered, and the organic phase is separated from the filtrate and evaporated. The residue was dissolved in 125 ml of methanol and combined with the solids in the filtrate. To the slurry, 125 ml of water was added dropwise, and then the mixture was stirred for 1.5 hours, followed by filtration. The filter cake was dried under vacuum at room temperature to give 46.3 (90% based on IVa) of Va. Recrystallization of a small portion of the product from methanol gives a sample with melting point and¹the HNMR spectrum is consistent with Va obtained in step b of example 1.

Example 7

Preparation of methyl (chlorocarbonyl) [4- (trifluoromethoxy) phenyl ] carbamate (Compound VII).

In a first reaction flask, 70.5 g (0.30 mol) of methyl 4- (trifluoromethoxy) phenylcarbamate were dissolved in 700 ml of dichloromethane. Then 14.0 g of 60% sodium hydride (0.35 mol) in mineral oil was added followed by 60 ml of glyme (ethylene glycol dimethyl ether) over 15 minutes. The reaction is exothermic and the temperature of the reaction mixture increases to slightly above room temperature. The reaction mixture was stirred overnight (about 16 hours) without external heat. In a second reaction flask equipped with a distillation column, 120 g (1.2 mol) of phosgene were dissolved in 300 ml of dichloromethane cooled to 5-10 ℃. The viscous slurry of the reaction mixture taken to the first flask was slowly added to the second flask containing the 5-10 ℃ phosgene solution. After the addition was complete, excess phosgene was removed by distillation until the head temperature indicated that only methylene chloride had occurred. The distillation was stopped and the reaction mixture was cooled to about 0 ℃.200 ml of ice water was added to dissolve the sodium chloride by-product. The dichloromethane layer was separated from the aqueous layer, filtered and dried over magnesium sulfate. The dried dichloromethane solution containing compound VII was then distilled off dichloromethane and replaced by addition of a total of 400 ml hexane (solvent exchange process). Distillation was stopped when the dichloromethane was removed and hexane distillation was started. The hexane solution was then cooled to 5 ℃ where VII precipitated (seeding may be required), recovered by filtration, washed with cold hexane and dried. The yield is generally about 94% of 97-98% pure VII, m.p.97-99 ℃.¹HNMR(CDCl₃)δ3.80(S，3)，7.29(S，4)。

Claims

1. The (+) enantiomer of a compound of the formula,

wherein,

R¹selected from the group consisting of F, Cl or C₁-C₃Fluoroalkoxy, and

R²is C₁-C₃An alkyl group.

2. The compound according to claim 1, which is (+) 5-chloro-1, 3-dihydro-2-hydroxy-1-oxo-2H-indene-2-carboxylic acid methyl ester.